Settling the score: variant prioritization and Mendelian disease

Area of Science:

• Genetics
• Bioinformatics
• Genomic Medicine

Background:

• Investigating Mendelian diseases with exome or genome sequencing generates numerous candidate genetic variants.
• Distinguishing pathogenic variants requires sophisticated analysis and interpretation strategies.
• Existing computational tools and clinical guidelines aid in variant prioritization but have limitations.

Purpose of the Study:

• To review the strengths and weaknesses of computational approaches for genetic variant prioritization.
• To explain the role of these tools in both clinical diagnostics and genetic discovery.
• To discuss the impact of whole-genome sequencing on variant interpretation.

Main Methods:

• Review of widely used computational variant prioritization tools.
• Analysis of existing clinical guidelines for variant interpretation.
• Discussion of genotype-phenotype association and gene prioritization methods.

Main Results:

• Computational tools offer valuable support but can also misinform expert reviewers.
• Variant prioritization is interconnected with gene prioritization and burden testing.
• Whole-genome sequencing presents new opportunities and challenges for variant interpretation.

Conclusions:

• Effective variant prioritization is crucial for accurate Mendelian disease diagnosis.
• Understanding the limitations of computational tools is essential for expert reviewers.
• Further development is needed to optimize variant interpretation in the era of whole-genome sequencing.